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Séminaire - François AmauryRVM GABAergic neurons command enkephalinergic spinal neurons to act as gatekeepers of mechanical pain.

Abstract :

 The spinal cord dorsal horn integrates information both from sensory neurons and the brain to shape pain experience. Specifically, populations of brainstem neurons in the rostral ventromedial medulla (RVM) project directly to the dorsal horn to facilitate or inhibit nociception as a function of emotional and internal states. This process is known as the descending control of pain. However, the stimuli and tasks that recruit RVM neurons to alter nociception in the dorsal horn, and the circuits involved, are largely unknown. Using viral tracing and electrophysiology, we identified a disynaptic brainstem-spinal cord circuit in which RVM neurons control enkephalin release in the dorsal horn to control pain. 

We found that a population of GABAergic neurons in the RVM inhibits spinal enkephalinergic interneurons in laminae I-III. We further demonstrate that these enkephalinergic neurons gate primary afferent inputs through temporally-coordinated presynaptic inhibition by enkephalins and GABA. Interestingly, despite their inhibitory nature, inhibition of these GABAergic RVM neurons facilitates pain, suggesting that they functionally correspond to a population of classical “ON cells”. To test this hypothesis, we use fiber photometry to record calcium activity in GABAergic RVM neurons in behaving mice submitted to a panel of sensory stimuli in different emotional and physiological states. Our results identify the key components of a circuit and the molecular steps by which activity in the brain can cause pain facilitation at the level of the spinal cord by controlling spinal endogenous opioid levels.

 

Selected publications

Wang D, Tawfik VL, Corder G, Low SA, François A, Basbaum AI, Scherrer G. Functional Divergence of Delta and Mu Opioid Receptor Organization in CNS Pain Circuits. Neuron. 2018 Apr 4 (ahead of print Mar 22); 98, 1–19 https://doi.org/10.1016/j.neuron.2018.03.002

François A, Low SA, Sypek EI, Christensen AJ, Sotoudeh C, Beier KT, Delp SL, Malenka RC, Luo L, Sharif-Naeini R, Ramakrishnan C, Deisseroth K, Hantman AW, Scherrer G. GABAergic Neurons of Rostral Ventromedial Medulla Facilitate Pain via a Dorsal Horn Disynaptic Inhibitory Circuit. Neuron. 2017 Feb 22;93(4):822-839.e6. PubMed PMID: 28162807.